Obesity is a major health problem in the United States. It increases the risk of insulin resistance (IR) and metabolic syndrome (MS), a cluster of cardiovascular disease (CVD) risk factors, and leads to additional pathologies, including non-alcoholic steatohepatitis (NASH), the second most common cause of liver cirrhosis;Alzheimer's disease;cardiomyopathy;cancer;and others, many associated with or exacerbated by aging. In principle, it should be simple to treat and prevent obesity with lifestyle modifications (diet and exercise) but these approaches have not worked well. It is therefore essential to develop innovative treatments for obesity and IR. Over the last ten years, it has become clear that obesity/IR is related to low- grade systemic inflammation and that the polarization state of adipose tissue macrophages (ATMs) is the important link between these seemingly disparate phenomena. Ml pro-inflammatory macrophages secrete factors that inhibit local and systemic insulin signaling whereas alternatively activated M2 macrophages counter the pro-inflammatory actions of Ml macrophages and enhance insulin sensitivity and blunt harmful effects of high fat diet. Recent data indicates that three nuclear receptors (NRs) are important for elaboration of M2 macrophage phenotype, peroxisome proliferator activated receptors (PPARs) y and 6 and estrogen receptor a (ERa). In addition, at least 20 other NRs are expressed in macrophages and effects of activation of these NRs in macrophage are unknown. In this proposal, we will assemble a team to understand the best way to selectively manipulate NR signaling in ATMs to inhibit metabolic disease while avoiding typical harmful side effects of NR ligands on the body. Our team brings together scientists from different institutions who are experts in NR actions in animal models of metabolic disease and macrophages, NR structure and molecular biology, chemical biology of NR action and NR genomics and natural NR ligands. We believe that this team will be well equipped to define ways to target macrophage NRs and develop new ligands to selectively manipulate NR signaling in this cell type and that the R24 mechanism will be perfect to help us form a team with a strong focus on chemical biology of NR action in macrophage. RELEVANCE: The nuclear receptors are an important protein family that is a well established target for drug development. 20% of current US prescriptions are for nuclear receptor ligands. Drugs that modulate activities of NRs in the macrophage could combat inflammation that contributes to insulin resistance, obesity and other aspects of metabolic syndrome, one of the biggest health problems facing the United States today.